Background: Depression is considered to be among the most significant causes of disability worldwide. Bipolar depression has been treated with the element Lithium since the late 19th century, although the mechanism of lithium action is still not known. A co-morbid relationship has often been described between bipolar depression and cardiovascular disease. Platelets are well known to be the main agents responsible for cardiovascular risk, and platelets of bipolar patients have been reported to have significant differences from platelets donated by controls. We have reported that platelets from bipolar patients exhibit a significantly activated protein kinase C signaling pathway, which is reversed by lithium treatment. [unreadable] Hypothesis: Based on these data, we hypothesize that bipolar depression affects multiple signaling processes in platelets. We anticipate that knowledge of how lithium repairs these dysfunctional platelet processes might help illuminate the mechanism of bipolar depression.[unreadable] Methods: We employed proteomic methods to analyze platelets and platelet subfractions from 20 patients with bipolar disorder, and from 20 age and sex-matched controls. Both patients and controls were treated with lithium for one month, and platelet samples were collected after one week and one month of treatment. Platelet membranes and cytosol were then analyzed by 2-DGE and silver-stained. Mass spectrometry was then used to identify differentially expressed proteins. Relative levels were quantitated by Progenesis software. [unreadable] Results: Preliminary data for platelet cytosol and membrane fractions have been collected from the first set of patients and controls. Two hundred ug each of cytosolic and membrane proteins, were isolated from platelets after one week and one month of lithium therapy. Analysis by 2DGE shows that changes occur over the time course of lithium treatment. Lithium effects are most profound in the membrane-rich fractions. So far proteins of interest are transferrin, moesin, dynamin-1 like protein and semenogelin 1. [unreadable] Conclusion: We conclude that meaningful significant interpretations must await for analysis of the complete disease and control cohort.